REBLOZYL Powder for solution for injection Ref.[10651] Active ingredients: Luspatercept

Pharmacotherapeutic group: Antianaemic preparations, other antianaemic preparations
ATC code: B03XA06

Mechanism of action

Luspatercept, an erythroid maturation agent, is a recombinant fusion protein that binds selected transforming growth factor-β (TGF-β) superfamily ligands. By binding to specific endogenous ligands (e.g. GDF-11, activin B) luspatercept inhibits Smad2/3 signalling, resulting in erythroid maturation through expansion and differentiation of late-stage erythroid precursors (normoblasts) in the bone marrow, thereby restoring effective erythropoiesis. Smad2/3 signalling is abnormally high in disease models characterised by ineffective erythropoiesis, i.e. MDS and β-thalassaemia, and in the bone marrow of MDS patients.

Somatic mutations in MDS patients

Luspatercept demonstrated clinical benefit and favourability over epoetin alfa across multiple genomic mutations that are frequently observed in lower-risk MDS with the exception of CBL gene mutations.

Clinical efficacy and safety

Myelodysplastic syndromes

The efficacy and safety of luspatercept were evaluated in a Phase 3 multicentre, randomised, open-label, active controlled study COMMANDS (ACE-536-MDS-002) comparing luspatercept versus epoetin alfa in patients with anaemia due to International Prognostic Scoring System-Revised (IPSS-R) very low-, low- or intermediate-risk MDS or with myelodysplastic/myeloproliferative neoplasm with ring sideroblasts and thrombocytosis (MDS/MPN RS-T) in ESA naïve patients (with endogenous sEPO levels of <500 U/L) who require red blood cell transfusions. For eligibility, patients were required to have had 2 to 6 RBC units/8 weeks confirmed for a minimum of 8 weeks immediately preceding randomization. Patients with deletion 5q (del5q) MDS were excluded from the study.

Patients were treated for at least 24 weeks, unless the patient experienced unacceptable toxicities, withdrew the consent or met any other treatment discontinuation criteria. The treatment was continued beyond week 24 in case of clinical benefit (defined as a transfusion reduction of ≥2 pRBC units/8 weeks compared with baseline) and absence of disease progression. Based on the outcome of these assessments, patients either were discontinued from treatment and entered into the Post-Treatment Follow-up Period or continued open-label treatment (with luspatercept or epoetin alfa) as long as the above criteria continued to be met or until the patient experienced unacceptable toxicities, withdrew consent, or met any other discontinuation criteria.

A total of 363 patients were randomized to receive subcutaneously luspatercept (N=182) or epoetin alfa (N=181) at 1 mg/kg every 3 weeks or at 450 U/kg every week, respectively. Randomization was stratified by RBC transfusion burden, RS status, and endogenous serum erythropoietin (sEPO) level at baseline. Two dose level increases were allowed for luspatercept (to 1.33 mg/kg and to 1.75 mg/kg). Doses were held and subsequently reduced for adverse reactions, reduced if the haemoglobin increased by ≥2 g/dL from the prior cycle, and held if the pre-dose haemoglobin was ≥12 g/dL. All patients received best supportive care, which included RBC transfusions, use of antibiotic, antiviral and antifungal therapy, and nutritional support as needed. BSC for this study excluded the use of ESAs outside of the study treatment. The key baseline disease characteristics in MDS patients in ACE-536-MDS-002 are shown in Table 8.

Table 8. Baseline demographics and disease characteristics of MDS patients in ACE-536-MDS-002:

Hb = haemoglobin; IPSSR = International Prognostic Scoring System-Revised; MDS-SLD = MDS with single lineage dysplasia; MDS-MLD = MDS with multilineage dysplasia; MDS-RS-SLD = MDS with ring sideroblasts with single lineage dysplasia; MDS-RS-MLD = MDS with ring sideroblasts with multilineage dysplasia; MDS/MPN-RS-T = myelodysplastic/myeloproliferative neoplasms with ring sideroblasts and thrombocytosis; RS+ = with ring sideroblasts; RS- = without ring sideroblasts; SF3B1 = Splicing Factor 3B Subunit 1A MDS mutation
^a Age was calculated based on the informed consent signing date.
^b After applying the 14/3-day rule (only Hb values that are measured at least 14 days after a transfusion may be used unless there is another transfusion within 3 days after the Hb assessment. If a transfusion within 3 days after the Hb assessment occurs, that Hb value will be used despite being <14 days after the previous transfusion), the baseline Hb value (efficacy) is defined as the lowest Hb value from the central, or local laboratory, or pre-transfusion Hb from transfusion records that is within the 35 days prior to the first dose of study drug, if it was available.
^c The number of months from the date of original diagnosis to the date of informed consent.
^d Baseline EPO was defined as the highest EPO value within the 35 days preceding the first dose of study drug.
^e Collected over 8 weeks prior to randomisation.

The efficacy results are summarised below.

Table 9. Efficacy results in MDS patients in ACE-536-MDS-002:

Hb = haemoglobin; RBC = red blood transfusion
^a Based on CMH test stratified by baseline RBC transfusion burden (<4, ≥4 pRBC units), RS status (RS+, RS-) and sEPO level (≤200, >200 U/L). 1-sided p-value is presented.
^b HI-E = haematological improvement – erythroid. The proportion of patients meeting the HI-E criteria as per International Working Group (IWG) 2006 criteria sustained over a consecutive 56-day period during the indicated treatment period. For patients with baseline RBC transfusion burden of ≥4 units/8 weeks, HI-E was defined as a reduction in RBC transfusion of at least 4 units/8 weeks. For patients with baseline RBC transfusion burden of <4 units/8 weeks, HI-E was defined as a mean increase in Hb of ≥1.5 g/dL for 8 weeks in the absence of RBC transfusions.
^c Nominal p-value

The treatment effect of luspatercept on RBC-TI ≥12 weeks and Hb increase of ≥1.5 g/dL was higher than epoetin alfa across all clinically relevant baseline demographic and most disease characteristic subgroups, except in patients without ring sideroblasts, where the treatment effect of luspatercept was comparable to epoetin alfa.

Myelodysplastic syndromes in ESA-refractory or -intolerant patients

The efficacy and safety of luspatercept were evaluated in a Phase 3 multicentre, randomised, double-blind, placebo-controlled study MEDALIST (ACE-536-MDS-001) in adult patients with anaemia requiring RBC transfusions (≥2 units/8 weeks) due to IPSS-R very low-, low- or intermediate-risk MDS who have ring sideroblasts (≥15%). Patients with del5q MDS or without ring sideroblasts (RS-) were not included in the study. Patients were required to have either received prior treatment with an ESA with inadequate response, to be ineligible for ESAs (determined to be unlikely to respond to ESA treatment with serum erythropoietin (EPO) >200 U/L), or intolerant to ESA treatment.

Patients in both arms were treated for 24 weeks, then continued treatment if they had demonstrated clinical benefit and absence of disease progression. The study was unblinded for analyses when all patients had at least received 48 weeks of treatment or discontinued treatment.

A total of 229 patients were randomised to receive luspatercept 1 mg/kg (N=153) or placebo (N=76) subcutaneously every 3 weeks. A total of 128 (83.7%) and 68 (89.5%) patients receiving luspatercept and placebo respectively completed 24 weeks of treatment. A total of 78 (51%) and 12 (15.8%) patients receiving luspatercept and placebo respectively completed 48 weeks of treatment. Dose titration up to 1.75 mg/kg was allowed. Dose could be delayed or reduced depending upon Hb level. All patients were eligible to receive best supportive care (BSC), which included RBC transfusions, iron-chelating agents, use of antibiotic, antiviral and antifungal therapy, and nutritional support, as needed. The key baseline disease characteristics in patients with MDS in study ACE-536-MDS-001 are shown in Table 10.

Table 10. Baseline demographics and disease characteristics of MDS patients with <5% marrow blasts in study ACE-536-MDS-001:

EPO = erythropoietin; Hb = haemoglobin; IPSS-R = International Prognostic Scoring System-Revised
^a Age was calculated based on the informed consent signing date.
^b Baseline EPO was defined as the highest EPO value within 35 days of the first dose of study drug.
^c Collected over 16 weeks prior to randomisation.
^d Baseline Hb was defined as the last value measured on or before the date of the first dose of investigational product (IP). After applying the 14/3-day rule, baseline Hb was defined as the lowest Hb value that was within 35 days on or prior to the first dose of IP.

The efficacy results are summarised below.

Table 11. Efficacy results in patients with MDS in study ACE-536-MDS-001:

RBC-TI: RBC Transfusion Independent; CI: confidence interval; CMH = Cochran-Mantel-Haenszel
^a CMH test stratified for average baseline transfusion burden (≥6 units vs. <6 units per 8 weeks), and baseline IPSS-R score (very low or low vs. intermediate).
^b After the Week 25 disease assessment visit, patients who were no longer deriving benefit discontinued therapy; few placebo patients contributed data for evaluation at the later timepoint compared with luspatercept (N=12 vs. N=78 respectively).
^c Post-hoc analysis using baseline imputation.

A treatment effect in favour of luspatercept over placebo was observed in most subgroups analysed using transfusion independence ≥12 weeks (during week 1 to week 24), including patients with high baseline endogenous EPO level (200-500 U/L) (23.3% vs. 0%, explorative analysis).

Only limited data are available for the group with transfusion burden of ≥8 units/8 weeks. Safety and efficacy have not been established in patients with a transfusion burden of >12 units/8 weeks.

Exploratory findings

Table 12. Exploratory efficacy results in patients with MDS in study ACE-536-MDS-001:

Hb = haemoglobin
^a mHI-E = modified haematological improvement – erythroid. The proportion of patients meeting the HI-E criteria as per International Working Group (IWG) 2006 criteria sustained over a consecutive 56-day period during the indicated treatment period. For patients with baseline RBC transfusion burden of ≥4 units/8 weeks, mHI-E was defined as a reduction in RBC transfusion of at least 4 units/8 weeks. For patients with baseline RBC transfusion burden of <4 units/8 weeks, mHI-E was defined as a mean increase in Hb of ≥1.5 g/dL for 8 weeks in the absence of RBC transfusions.
^b If a patient did not have a serum ferritin value within the designated postbaseline interval, the serum ferritin is imputed from the baseline value.
^c Analysis of covariance was used to compare the treatment difference between groups (including nominal p-value), with the change in serum ferritin as the dependent variable, treatment group (2 levels) as a factor, and baseline serum ferritin value as covariates, stratified by average baseline RBC transfusion requirement (≥6 units vs. <6 units of RBC per 8 weeks), and baseline IPSS-R (very low or low vs. intermediate).

The median duration of the longest RBC Transfusion Independent (RBC-TI) period among responders in the luspatercept treatment arm was 30.6 weeks.

A total of 62.1% (36/58) of the luspatercept responders who achieved RBC-TI ≥8 weeks from Weeks 1-24 had 2 or more episodes of RBC-TI at the time of analysis.

Transfusion-dependent β-thalassaemia

The efficacy and safety of luspatercept were evaluated in a Phase 3 multicentre, randomised, double-blind, placebo-controlled study BELIEVE (ACE-536-B-THAL-001) in adult patients with transfusion-dependent β-thalassaemia–associated anaemia who require RBC transfusions (6-20 RBC units/24 weeks) with no transfusion-free period >35 days during that period.

Patients in both the luspatercept and placebo arms were treated for at least 48 and up to 96 weeks. After unblinding, placebo patients were able to cross-over to luspatercept.

A total of 336 adult patients were randomised to receive luspatercept 1 mg/kg (N=224) or placebo (N=112) subcutaneously every 3 weeks. Dose titration to 1.25 mg/kg was allowed. Dose could be delayed or reduced depending upon Hb level. All patients were eligible to receive BSC, which included RBC transfusions, iron-chelating agents, use of antibiotic, antiviral and antifungal therapy, and nutritional support, as needed. The study excluded patients with Hb S/β-thalassaemia or alpha (α)-thalassaemia or who had major organ damage (liver disease, heart disease, lung disease, renal insufficiency). Patients with recent DVT or stroke or recent use of ESA, immunosuppressant or hydroxyurea therapy were also excluded. The key baseline disease characteristics in patients with β-thalassaemia in study ACE-536-B-THAL-001 are shown in Table 13.

Table 13. Baseline demographics and disease characteristics of patients with transfusion-dependent β-thalassaemia in study ACE-536-B-THAL-001:

^a The 12-week pretransfusion threshold was defined as the mean of all documented pretransfusions Hb values for a patient during the 12 weeks prior to Cycle 1 Day 1.
^b "Missing" category includes patients in the population who had no result for the parameter listed.

The study was unblinded for analyses when all patients had at least received 48 weeks of treatment or discontinued treatment.

The efficacy results are summarised below.

Table 14. Efficacy results in patients with transfusion-dependent β-thalassaemia in study ACE-536-B-THAL-001:

CI: confidence interval.
^a Difference in proportions (luspatercept + BSC – placebo + BSC) and 95% CIs estimated from the unconditional exact test.
^b P-value from the Cochran Mantel-Haenszel test stratified by the geographical region.

Exploratory findings

Table 15. Exploratory efficacy results in patients with transfusion-dependent β-thalassaemia in study ACE-536-B-THAL-001:

Difference in proportions (95% CI)^a |\2<> 22.8 (16.5, 29.1) |
|\3< Least square (LS) mean change from baseline in transfusion burden (RBC units/48 weeks) |
| Weeks 1 to Week 48
LS mean |<>
-4.69|<>
+1.17 |
|LS mean of difference (luspatercept-placebo) |\2<> -5.86 |
| (95% CI)^b |\2<> (-7.04, -4.68) |
| Weeks 49 to Week 96
LS mean|<>
-5.43|<>
+1.80 |
|LS mean of difference (luspatercept-placebo) |\2<> -7.23 |
| (95% CI)^b |\2<> (-13.84, -0.62) |

ANCOVA = analysis of covariance; CI: confidence interval.
^a Difference in proportions (luspatercept + BSC – placebo + BSC) and 95% CIs estimated from the unconditional exact test.
^b Estimates are based on ANCOVA model with geographical regions and baseline transfusion burden as covariates.
^* Placebo patients are assessed up to prior to crossing over to luspatercept. For the rolling analyses at any consecutive 12/24 weeks, luspatercept treatment arm does not include placebo patients who crossed over to luspatercept.

A reduction in mean serum ferritin levels was observed from baseline in the luspatercept arm compared to an increase in the placebo arm at Week 48 (-235.56 mcg/L vs. +107.03 mcg/L which resulted in a least square mean treatment difference of -342.59 mcg/L (95% CI: -498.30, -186.87).

A total of 85% (147/173) of luspatercept responders who achieved at least a 33% reduction in transfusion burden during any consecutive 12-week interval achieved 2 or more episodes of response at the time of analysis.

Non-transfusion-dependent β-thalassaemia

The efficacy and safety of luspatercept were evaluated in a Phase 2 multicentre, randomised, double-blind, placebo-controlled study BEYOND (ACE-536-B-THAL-002) in adult patients with non-transfusion-dependent β-thalassaemia-associated anaemia (Hb concentration ≤10 g/dL).

A total of 145 adult patients receiving RBC transfusions (0-5 RBC units in the 24-week period prior to randomization), with a baseline Hb level ≤10 g/dL (defined as average of at least 2 Hb measurements ≥1 week apart within 4 weeks prior to randomization) were randomized to receive luspatercept (N=96) or placebo (N=49) subcutaneously every 3 weeks. Patients were stratified at randomization based on their baseline Hb level and their non-transfusion-dependent β-thalassaemia (NTDT) patient-reported outcome (PRO; NTDT-PRO) Tiredness/Weakness (T/W) weekly domain score. Dose titration to 1.25 mg/kg was allowed. Dose could be delayed or reduced depending upon Hb level. Overall, 53% of luspatercept patients (N=51) and 92% of patients on placebo (N=45) had their dose increased to 1.25 mg/kg within the 48-week treatment period. Among patients receiving luspatercept, 96% were exposed for 6 months or longer and 86% were exposed for 12 months or longer. A total of 89 (92.7%) patients receiving luspatercept and 35 (71.4%) patients receiving placebo completed 48 weeks of treatment.

All patients were eligible to receive BSC, which included RBC transfusions, iron-chelating agents, use of antibiotic, antiviral, and antifungal therapy, and nutritional support, as needed. Concurrent treatment for anaemia with blood transfusions was allowed, at the discretion of the physician, for low haemoglobin levels, symptoms associated with anaemia (e.g. haemodynamic or pulmonary compromise requiring treatment) or comorbidities. The study excluded patients with Hb S/β-thalassaemia or alpha (α)-thalassaemia or who had major organ damage (liver disease, heart disease, lung disease, renal insufficiency), active hepatitis C or B, or HIV. Patients with recent DVT or stroke or recent use of ESA, immunosuppressant or hydroxyurea therapy, or on chronic anticoagulant or uncontrolled hypertension were also excluded. Only a limited number of patients with comorbidities associated with underlying anaemia such as pulmonary hypertension, liver and kidney disease and diabetes were included in the study.

The key baseline disease characteristics in the Intention-To-Treat (ITT) population with non-transfusion-dependent β-thalassaemia in study ACE-536-B-THAL-002 are shown in Table 16.

Table 16. Baseline demographics and disease characteristics of patients with non-transfusion-dependent β-thalassaemia in study ACE-536-B-THAL-002:

Hb = haemoglobin; HbE = haemoglobin E; ICT = Iron Chelation Therapy; LIC = liver iron concentration; max = maximum; min = minimum; MRI = magnetic resonance imaging; NTDT-PRO T/W = non-transfusion-dependent β-thalassaemia patient-reported outcome tiredness and weakness domain score;
^a Mean of at least 2 Hb values by the central laboratory during the 28-day screening period.
^b Baseline defined as the average of non-missing NTDT-PRO T/W domain score over 7 days before Dose 1 Day 1.
^c The value of LIC was either the value collected from the electronic Case Report Form (eCRF) or the value derived from T2*, R2*, or R2 parameter depending on which techniques and software were used for MRI LIC acquisition.
^d Baseline mean serum ferritin was calculated during the 24 weeks on or prior to Dose 1 Day 1. Baseline ICT was calculated during the 24 weeks on or prior to Dose 1 Day 1.

The efficacy results are summarised below.

Table 17. Efficacy results in patients with non-transfusion-dependent β-thalassaemia in study ACE-536-B-THAL-002:

CI = confidence interval; Hb = haemoglobin
^a Defined as number of patients with ≥1 g/dL Hb increase in the absence of RBC transfusion compared to baseline (i.e. the average of ≥2 Hb measurements at ≥1 week apart within 4 weeks before Dose 1 Day 1).
^b The 95% CI for response rate (%) was estimated from the Clopper-Pearson exact test.
^c The odds ratio (luspatercept vs. placebo) with 95% CI and p-value were estimated from the CMH test stratified by baseline Hb category (<8.5 vs. ≥8.5 g/dL) and baseline NTDT-PRO T/W domain score category (≥3 vs. <3) defined at randomization as covariates.
Note: Patients with missing Hb at Weeks 13-24 were classified as non-responders in the analysis.

A total of 77.1% of luspatercept treated patients achieved an increase from baseline ≥1 g/dL in mean Hb over continuous 12-week interval (in absence of transfusions) (Weeks 13-24). This effect was maintained in the 57.3% of patients who reached Week 144 of treatment.

Paediatric population

Myelodysplastic syndromes

The European Medicines Agency has waived the obligation to submit the results of studies with Reblozyl in all subsets of the paediatric population in myelodysplastic syndromes (see section 4.2 for information on paediatric use).

β-thalassaemia

The European Medicines Agency has deferred the obligation to submit the results of studies with Reblozyl in one or more subsets of paediatric population older than 6 years of age in β-thalassaemia (see section 4.2 for information on paediatric use).